NCCN Categories of Evidence and Consensus
Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.
Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.
All recommendations are category 2A unless otherwise noted.
Clinical trials: NCCN believes that the best management for any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
NCCN defines cancer-related fatigue as “a distressing, persistent, subjective sense of physical, emotional, and/or cognitive tiredness or exhaustion related to cancer or cancer treatment that is not proportional to recent activity and interferes with usual functioning.”1 Fatigue is a common symptom in patients with cancer and is nearly universal in those receiving cytotoxic chemotherapy, radiation therapy, bone marrow transplantation, or treatment with biological response modifiers.2-4 According to a survey of 1569 patients with cancer, the symptom is experienced by 80% of individuals who receive chemotherapy and/or radiotherapy.5,6 Cancer survivors report that fatigue continues to be a disruptive symptom after treatment ends,7-14 with studies showing that 17% to 29% of cancer survivors experience persistent fatigue for years after the completion of active therapy.15,16 Persistent cancer-related fatigue affects quality of life, because individuals become too tired to fully participate in the roles and activities that make life meaningful.9,17 Disability-related issues are also relevant for cancer survivors, because obtaining or retaining disability benefits from insurers is often difficult for patients with cancer-related fatigue. Identification and management of fatigue remains an unmet need for many cancer survivors.
The specific mechanisms involved in the pathophysiology of cancer-related fatigue are unknown. Proposed mechanisms include proinflammatory cytokines, hypothalamic-pituitary-adrenal axis dysregulation, circadian rhythm desynchronization, skeletal muscle wasting, and genetic dysregulation.18-23 Several studies have focused on the cause of fatigue, especially in cancer survivors with no evidence of active disease, and have suggested that persistent immune system activation and chronic inflammatory processes may be involved.7,24-26 Evidence supporting these mechanisms is limited.
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Haghighat S, Akbari ME, Holakouei K et al. . Factors predicting fatigue in breast cancer patients. Support Care Cancer 2003;11:533–538.
Ruffer JU, Flechtner H, Tralls P et al. . Fatigue in long-term survivors of Hodgkin’s lymphoma; a report from the German Hodgkin Lymphoma Study Group (GHSG). Eur J Cancer 2003;39:2179–2186.
Servaes P, Verhagen S, Bleijenberg G. Determinants of chronic fatigue in disease-free breast cancer patients: a cross-sectional study. Ann Oncol 2002;13:589–598.
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Wang XS, Zhao F, Fisch MJ et al. . Prevalence and characteristics of moderate to severe fatigue: A multicenter study in cancer patients and survivors. Cancer 2014;120:425–432.
Janda M, Gerstner N, Obermair A et al. . Quality of life changes during conformal radiation therapy for prostate carcinoma. Cancer 2000;89:1322–1328.
al-Majid S, McCarthy DO. Cancer-induced fatigue and skeletal muscle wasting: the role of exercise. Biol Res Nurs 2001;2:186–197.
Berger AM, Wielgus K, Hertzog M et al. . Patterns of circadian activity rhythms and their relationships with fatigue and anxiety/depression in women treated with breast cancer adjuvant chemotherapy. Support Care Cancer 2009;18:105–114.
Bower JE. Cancer-related fatigue: links with inflammation in cancer patients and survivors. Brain Behav Immun 2007;21:863–871.
Miller AH, Ancoli-Israel S, Bower JE et al. . Neuroendocrine-immune mechanisms of behavioral comorbidities in patients with cancer. J Clin Oncol 2008;26:971–982.
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Alfano CM, Imayama I, Neuhouser ML et al. . Fatigue, inflammation, and omega-3 and omega-6 fatty acid intake among breast cancer survivors. J Clin Oncol 2012;30:1280–1287.
Bower JE, Ganz PA, Irwin MR et al. . Inflammation and behavioral symptoms after breast cancer treatment: do fatigue, depression, and sleep disturbance share a common underlying mechanism? J Clin Oncol 2011;29:3517–3522.
Bower JE, Ganz PA, Aziz N, Fahey JL. Fatigue and proinflammatory cytokine activity in breast cancer survivors. Psychosom Med 2002;64:604–611.
Mendoza TR, Wang XS, Cleeland CS et al. . The rapid assessment of fatigue severity in cancer patients: use of the Brief Fatigue Inventory. Cancer 1999;85:1186–1196.
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Brown JC, Huedo-Medina TB, Pescatello LS et al. . Efficacy of exercise interventions in modulating cancer-related fatigue among adult cancer survivors: a meta-analysis. Cancer Epidemiol Biomarkers Prev 2011;20:123–133.
Courneya KS, Mackey JR, Bell GJ et al. . Randomized controlled trial of exercise training in postmenopausal breast cancer survivors: cardiopulmonary and quality of life outcomes. J Clin Oncol 2003;21:1660–1668.
Mishra SI, Scherer RW, Geigle PM et al. . Exercise interventions on health-related quality of life for cancer survivors. Cochrane Database Syst Rev 2012;8:CD007566.
McMillan EM, Newhouse IJ. Exercise is an effective treatment modality for reducing cancer-related fatigue and improving physical capacity in cancer patients and survivors: a meta-analysis. Appl Physiol Nutr Metab 2011;36:892–903.
McNeely ML, Campbell KL, Rowe BH et al. . Effects of exercise on breast cancer patients and survivors: a systematic review and meta-analysis. CMAJ 2006;175:34–41.
McNeely ML, Courneya KS. Exercise programs for cancer-related fatigue: evidence and clinical guidelines. J Natl Compr Canc Netw 2010;8:945–953.
Speck RM, Courneya KS, Masse LC et al. . An update of controlled physical activity trials in cancer survivors: a systematic review and meta-analysis. J Cancer Surviv 2010;4:87–100.
Cramp F, Byron-Daniel J. Exercise for the management of cancer-related fatigue in adults. Cochrane Database Syst Rev 2012;11:CD006145.
Duijts SF, Faber MM, Oldenburg HS et al. . Effectiveness of behavioral techniques and physical exercise on psychosocial functioning and health-related quality of life in breast cancer patients and survivors: a meta-analysis. Psychooncology 2011;20:115–126.
Espie CA, Fleming L, Cassidy J et al. . Randomized controlled clinical effectiveness trial of cognitive behavior therapy compared with treatment as usual for persistent insomnia in patients with cancer. J Clin Oncol 2008;26:4651–4658.
Epstein DR, Dirksen SR. Randomized trial of a cognitive-behavioral intervention for insomnia in breast cancer survivors. Oncol Nurs Forum 2007;34:E51–59.
Gielissen MFM, Verhagen S, Witjes F, Bleijenberg G. Effects of cognitive behavior therapy in severely fatigued disease-free cancer patients compared with patients waiting for cognitive behavior therapy: a randomized controlled trial. J Clin Oncol 2006;24:4882–4887.
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Dirksen SR, Epstein DR. Efficacy of an insomnia intervention on fatigue, mood and quality of life in breast cancer survivors. J Adv Nurs 2008;61:664–675.
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Barton DL, Liu H, Dakhil SR et al. . Wisconsin Ginseng (Panax quinquefolius) to improve cancer-related fatigue: a randomized, double-blind trial, N07C2. J Natl Cancer Inst 2013;105:1230–1238.